rs2304935

Variant names:

• chr11-60334911-A-G
• rs2304935
• NM_139249.4:c.16A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_139249.4(MS4A6E):​c.16A>G​(p.Ile6Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 1,609,964 control chromosomes in the GnomAD database, including 89,858 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.32 (8425 hom., cov: 32)
  • Exomes 𝑓: 0.33 (81433 hom.)
• Consequence: MS4A6E NM_139249.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.775
• Publications: 28 publications found

Genes affected

MS4A6E (HGNC:14285): (membrane spanning 4-domains A6E) This gene encodes a member of the membrane-spanning 4A gene family. Members of this nascent protein family are characterized by common structural features and similar intron/exon splice boundaries and display unique expression patterns among hematopoietic cells and nonlymphoid tissues. The gene encoding this protein is localized to 11q12.3, among a cluster of family members. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.984567E-5).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.354 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MS4A6E	NM_139249.4	c.16A>G	p.Ile6Val	missense_variant	Exon 2 of 5	ENST00000684409.1	NP_640342.1
MS4A6E	NR_170614.1	n.184A>G		non_coding_transcript_exon_variant	Exon 2 of 6
MS4A6E	NR_170615.1	n.184A>G		non_coding_transcript_exon_variant	Exon 2 of 5
MS4A6E	NR_170616.1	n.184A>G		non_coding_transcript_exon_variant	Exon 2 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MS4A6E	ENST00000684409.1	c.16A>G	p.Ile6Val	missense_variant	Exon 2 of 5		NM_139249.4	ENSP00000507799.1
MS4A6E	ENST00000300182.8	c.16A>G	p.Ile6Val	missense_variant	Exon 1 of 4	1		ENSP00000300182.4
MS4A6E	ENST00000530509.1	n.-66A>G		upstream_gene_variant		3		ENSP00000436675.1
MS4A6E	ENST00000532756.1	n.-60A>G		upstream_gene_variant		4		ENSP00000432963.1

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48590 AN: 151926 Hom.: 8403 Cov.: 32

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.288

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.265

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.293

GnomAD2 exomes AF: 0.324 AC: 81521 AN: 251412 AF XY: 0.315

Gnomad AFR exome AF: 0.251

Gnomad AMR exome AF: 0.385

Gnomad ASJ exome AF: 0.247

Gnomad EAS exome AF: 0.269

Gnomad FIN exome AF: 0.559

Gnomad NFE exome AF: 0.337

Gnomad OTH exome AF: 0.306

GnomAD4 exome AF: 0.326 AC: 475580 AN: 1457920 Hom.: 81433 Cov.: 36 AF XY: 0.321 AC XY: 232571 AN XY: 725490

African (AFR) AF: 0.249 AC: 8327 AN: 33428

American (AMR) AF: 0.378 AC: 16891 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 6586 AN: 26108

East Asian (EAS) AF: 0.299 AC: 11847 AN: 39688

South Asian (SAS) AF: 0.149 AC: 12836 AN: 86182

European-Finnish (FIN) AF: 0.544 AC: 29056 AN: 53408

Middle Eastern (MID) AF: 0.192 AC: 1104 AN: 5764

European-Non Finnish (NFE) AF: 0.334 AC: 370683 AN: 1108346

Other (OTH) AF: 0.303 AC: 18250 AN: 60282

GnomAD4 genome AF: 0.320 AC: 48655 AN: 152044 Hom.: 8425 Cov.: 32 AF XY: 0.328 AC XY: 24367 AN XY: 74324

African (AFR) AF: 0.252 AC: 10439 AN: 41470

American (AMR) AF: 0.362 AC: 5534 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 935 AN: 3468

East Asian (EAS) AF: 0.265 AC: 1370 AN: 5174

South Asian (SAS) AF: 0.151 AC: 727 AN: 4826

European-Finnish (FIN) AF: 0.570 AC: 6011 AN: 10538

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.334 AC: 22706 AN: 67978

Other (OTH) AF: 0.295 AC: 623 AN: 2110

Alfa AF: 0.315 Hom.: 26338

Bravo AF: 0.304

TwinsUK AF: 0.343 AC: 1272

ALSPAC AF: 0.328 AC: 1264

ESP6500AA AF: 0.260 AC: 1144

ESP6500EA AF: 0.336 AC: 2888

ExAC AF: 0.318 AC: 38658

Asia WGS AF: 0.224 AC: 778 AN: 3478

EpiCase AF: 0.302

EpiControl AF: 0.303

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.88	T
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.0060
DANN	Benign	0.18
DEOGEN2	Benign	0.00025	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0012	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.000070	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.69	N
PhyloP100		-0.78
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.23	N
REVEL	Benign	0.027
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.012
MPC		0.030
ClinPred		0.00083	T
GERP RS		-3.9
PromoterAI		0.041	Neutral
Varity_R		0.016
gMVP		0.071
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2304935; hg19: chr11-60102384; COSMIC: COSV55726900; COSMIC: COSV55726900;